title: AHI-1 interacts with BCR-ABL and modulates BCR-ABL transforming activity and imatinib response of CML stem/progenitor cells.
abstract: Chronic myeloid leukemia (CML) represents the first human malignancy successfully treated with a tyrosine kinase inhibitor (TKI; imatinib). However, early relapses and the emergence of imatinib-resistant disease are problematic. Evidence suggests that imatinib and other inhibitors may not effectively eradicate leukemic stem/progenitor cells, and that combination therapy directed to complimentary targets may improve treatment. Abelson helper integration site 1 (Ahi-1)/AHI-1 is a novel oncogene that is highly deregulated in CML stem/progenitor cells where levels of BCR-ABL transcripts are also elevated. Here, we demonstrate that overexpression of Ahi-1/AHI-1 in murine and human hematopoietic cells confer growth advantages in vitro and induce leukemia in vivo, enhancing effects of BCR-ABL. Conversely, RNAi-mediated suppression of AHI-1 in BCR-ABL-transduced lin(-)CD34(+) human cord blood cells and primary CML stem/progenitor cells reduces their growth autonomy in vitro. Interestingly, coexpression of Ahi-1 in BCR-ABL-inducible cells reverses growth deficiencies exhibited by BCR-ABL down-regulation and is associated with sustained phosphorylation of BCR-ABL and enhanced activation of JAK2-STAT5. Moreover, we identified an AHI-1-BCR-ABL-JAK2 interaction complex and found that modulation of AHI-1 expression regulates phosphorylation of BCR-ABL and JAK2-STAT5 in CML cells. Importantly, this complex mediates TKI response/resistance of CML stem/progenitor cells. These studies implicate AHI-1 as a potential therapeutic target downstream of BCR-ABL in CML.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver V5Z 1L3, BC, Canada.
authors.forename: Liang L
authors.initials: LL
authors.lastname: Zhou
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ashley
authors.initials: A
authors.lastname: Ringrose
authors.forename: Donna
authors.initials: D
authors.lastname: DeGeer
authors.forename: Erin
authors.initials: E
authors.lastname: Kennah
authors.forename: Ann E-J
authors.initials: AE
authors.lastname: Lin
authors.forename: Guoqing
authors.initials: G
authors.lastname: Sheng
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Li
authors.forename: Ali
authors.initials: A
authors.lastname: Turhan
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Jiang
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001549:Benzamides; D015153:Blotting, Western; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D047468:Immunoprecipitation; D053614:Janus Kinase 2 / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D010879:Piperazines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C465818:Ahi1 protein, mouse; D001549:Benzamides; D017931:DNA Primers; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D053614:Janus Kinase 2